Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2

Gaubitz, Christl; Oliveira, Taiana M; Prouteau, Manoel; Leitner, Alexander; Karuppasamy, Manikandan; Konstantinidou, Georgia; Rispal, Delphine; Eltschinger, Sandra; Robinson, Graham C; Thore, Stéphane; Aebersold, Ruedi; Schaffitzel, Christiane; Loewith, Robbie Joséph

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Title		Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2
Authors		Gaubitz, Christl Oliveira, Taiana M Prouteau, Manoel Leitner, Alexander Karuppasamy, Manikandan Konstantinidou, Georgia Rispal, Delphine Eltschinger, Sandra Robinson, Graham C Thore, Stéphane Aebersold, Ruedi Schaffitzel, Christiane Loewith, Robbie Joséph show all authors [1 - 13]
Published in		Molecular Cell. 2015, vol. 58, no. 6, p. 977-988
Abstract		Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression.
Keywords		Antifungal Agents/metabolism/pharmacology — Binding Sites/genetics — Biocatalysis/drug effects — Blotting — Western — Carrier Proteins/chemistry/genetics/metabolism — Cell Cycle/drug effects/genetics — Cell Cycle Proteins/chemistry/genetics/metabolism — Drug Resistance/genetics — Mass Spectrometry/methods — Mechanistic Target of Rapamycin Complex 2 — Microscopy — Electron — Multiprotein Complexes/chemistry/genetics/metabolism — Mutation — Phosphatidylinositol 3-Kinases/chemistry/genetics/metabolism — Protein Structure — Tertiary — Saccharomyces cerevisiae/drug effects/genetics/metabolism — Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/ultrastructure — Sirolimus/metabolism/pharmacology — TOR Serine-Threonine Kinases/chemistry/genetics/metabolism
Identifiers		DOI: 10.1016/j.molcel.2015.04.031 PMID: 26028537
Full text		Article (Published version) (3.2 MB) - Limited access to UNIGE
Structures		Faculté des sciences / Section de biologie / Département de biologie moléculaire Centres et instituts / Institut de génétique et de génomique
Research group		Groupe Loewith
Citation (ISO format)		GAUBITZ, Christl et al. Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2. In: Molecular Cell, 2015, vol. 58, n° 6, p. 977-988. https://archive-ouverte.unige.ch/unige:103227